Precocious puberty: diagnosis and management

Precocious puberty is commonly defined as puberty that starts before age 8 years in girls and 9 years in boys. The causes of it may range from a variant of normal development to various pathologic conditions. The etiology of precocious puberty is classified by the underlying pathogenesis into gonadotropin dependent central precocious puberty and peripheral precocious puberty which is independent of gonadotropin but due to different other causes. Variants of precocious puberty include premature thelarche, premature puberche and isolated premature menarche which imply onset of isolated changes without any other signs of sexual development. Precocious puberty might have an impact on final stature owing to premature epiphyseal fusion and also it has got influence on psychosocial wellbeing. Evaluation includes a detailed history, physical examination, biochemical testing and imaging directed towards suspected etiology. Gonadotropin releasing hormone (GnRH) analogues are effective for treatment of central precocious puberty. Treatment of peripheral precocious puberty should be based on the specific cause. Pubertal variants are usually non-progressive and need no treatment but should be monitored carefully. BIRDEM Med J 2022; 12(1): 62-69

Assessment of gonadotropin concentrations stimulated by gonadotropin-releasing hormone analog by electrochemiluminescence (ECLIA) in girls with precocious puberty and premature thelarche

Objective: The aim of this study is to determine the cutoff values of gonadotropin response to gonadotropin-releasing hormone analogs (GnRHas) corresponding to the activation of the hypothalamic–pituitary–gonadal axis that could differentiate central precocious puberty (CPP) from premature thelarche (PT) and using the electrochemiluminescence assay method. Methods: A total of 49 girls underwent the stimulation test with the intramuscular injection of 3.75 mg leuprolide acetate. Based on the clinical and laboratory characteristics, they were divided into two groups: CPP (n = 22) and PT (n = 27). Baseline estradiol, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were collected before GnRHa administration, and LH and FSH at 60 and 120 min, respectively, after GnRHa administration. Results: The girls with CPP presented an increased height Z-score, advanced bone age, and higher baseline LH, FSH, estradiol, and LH/FSH ratio in relation to PT (p < 0.001). Stimulated LH differed significantly between the two groups, and the LH cutoff values were ≥4.29 IU/L (p < 0.001) and ≥3.95 IU/L at 60 and 120 min, respectively (p < 0.001). LH peak was found at 60 min after stimulation. Conclusions: The GnRHa test is effective in distinguishing CPP from PT, and a single sampling, at 60 min, with LH concentrations above 4.29 may be the parameter of choice with the advantage of greater convenience and practicality.

Possible role of melatonin in precocious and accelerated puberty in females during the COVID-19 pandemic

BackgroundPubertal development is a complex process influenced by a multitude of factors; among these, the role of melatonin has only been partially investigated. During the COVID-19 pandemic an unexpected increase in cases of precocious and fast puberty was observed.AimsTo evaluate the possible role of salivary melatonin in precocious and accelerated puberty during the COVID-19 lockdown.Patients and MethodsFifty-four females were evaluated from October 2020 to March 2021; of these, 39 children were diagnosed with central precocious puberty (CPP) and 15 with isolated premature thelarche (IPT). Thirty-three healthy children acted as controls. The enrolled patients were asked to take measures the day before the visit to avoid influencing readings of melatonin secretion. Salivary melatonin levels were analyzed using commercially available ELISA kit.ResultsThere was no difference in the time from B2 to diagnosis (months) between IPT and CPP patients. However, the anamnestic and clinical data of our CPP patients confirmed an acceleration in the stages of pubertal development. As expected, subjects with CPP showed a significantly greater stature SDS and height velocity SDS. There were no differences in BMI SDS and Delta BMI SDS. Interestingly, we discovered a significant difference regarding the use of electronic devices between children with CPP, IPT and controls (p < 0.05). Children with CPP showed significantly lower values of salivary melatonin than patients with TPT and controls (p < 0.0001).DiscussionOur results showed a marked reduction in salivary melatonin in children with CPP diagnosed during and after lockdown for COVID-19. Larger studies are needed to confirm and investigate these findings.

Diagnostic Accuracy of Female Pelvic Ultrasonography in Differentiating Precocious Puberty From Premature Thelarche: A Systematic Review and Meta-analysis

BackgroundThe gonadotropin-releasing hormone (GnRH) stimulation test is the benchmark for diagnosing precocious puberty (PP). However, it is invasive, time-consuming, costly, and may create an unpleasant experience for participants. Moreover, some overlaps may occur between PP and premature thelarche (PT) in the early stage of PP. Female pelvic ultrasonography may provide additional information to help differentiate PP from PT and subsequently initiate early treatment. In this study, we aimed to first directly compare pelvic ultrasonography parameters between PP and PT groups and secondly, investigate their diagnostic accuracy compared with the GnRH stimulation test.MethodsA systematic search of the PubMed/MEDLINE, EMBASE, Scopus, and Cochrane Library databases was performed up to March 31, 2021. All types of studies, except for case reports and review articles, were included. The GnRH stimulation test was used to confirm PP diagnosis. Those whose organic conditions might cause PP were excluded. The mean, standard deviation, sensitivity, and specificity of each parameter were documented. Forest plots were constructed to display the estimated standardized mean differences (SMDs) from each included study and the overall calculations. A bivariate model was used to calculate the pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR).ResultsA total of 13 studies were included for analysis. The SMDs (95% confidence interval – CI) in ovarian volume, fundal-cervical ratio, uterine length, uterine cross-sectional area, and uterine volume between PP and PT groups were 1.12 (0.78–1.45; p &lt; 0.01), 0.90 (0.07–1.73; p = 0.03), 1.38 (0.99–1.78; p &lt; 0.01), 1.06 (0.61–1.50; p &lt; 0.01), and 1.21 (0.84–1.58; p &lt;0.01), respectively. A uterine length of 3.20 cm yielded a pooled sensitivity of 81.8% (95% CI 78.3%–84.9%), specificity of 82.0% (95% CI 61.0%–93.0%), PLR of 4.56 (95% CI 2.15–9.69), NLR of 0.26 (95% CI 0.17–0.39), and DOR of 19.62 (95% CI 6.45–59.68). The area under the summary receiver operating characteristics curve was 0.82.ConclusionFemale pelvic ultrasonography may serve as a complementary tool to the GnRH stimulation test in differentiating PP from PT.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021232427, ID: CRD42021232427.

The effect of GnRH stimulation on AMH regulation in central precocious puberty and isolated premature thelarche

Objectives There is a complex interaction between the anti-müllerian hormone (AMH) and hypothalamic–pituitary–gonadal axis. However, the effect of gonadotropin-releasing hormone (GnRH) stimulation on AMH levels is not clearly known. In the study, we aimed to evaluate the effect of GnRH stimulation on AMH levels in central precocious puberty (CPP) and isolated premature thelarche (PT) groups. Methods Sixty-three girls with breast development before the age of 8 were enrolled in the study. GnRH test was performed on all subjects. Blood samples for follicle-stimulating hormone (FSH), luteinizing hormone (LH), and AMH levels were taken at basal, 40th, and 90th minute of GnRH test. Subjects were grouped as CPP and PT group. Results After GnRH stimulation, AMH levels increased significantly at the 40th minute and the stimulating effect of GnRH on AMH continued till the 90th minute (p: 0.0001). There was a positive correlation between basal and 90th-minute AMH levels (r: 479, p: 0.0001). The highest FSH, LH, and AMH times were significantly different after the GnRH stimulation (p: 0.001, p: 0.001, and p: 0.007). Although the CPP group had a lower basal AMH level than the PT group’s basal AMH level; AMH response to GnRH stimulation was not different (p>0.05). Conclusions In our study, which examined the effect of GnRH stimulation on AMH levels in early pubertal development disorders for the first time, GnRH stimulated AMH secretion rapidly, correlated with basal AMH. Basal AMH levels were lower in patients with CPP than in those with PT; however, the effect of GnRH stimulation on AMH levels was similar in both groups.

The role of kisspeptin and MKRN3 in the diagnosis of central precocious puberty in girls

Objective: To evaluate the characteristics and significance of serum kisspeptin and MKRN3 levels for the diagnostic of central precocious puberty (CPP) in girls. Method: 34 individuals with CPP, 17 individuals with premature thelarche (PT) and 28 age-matched prepubertal girls as normal control (NC) were recruited in this case-control study. Physical measurements included of body mass index and tests for breast, bone and sexual characteristics were carried out. Biochemical measurements included serum LH, FSH, estradiol, insulin-like growth factor-1, MKRN3 and kisspeptin. Blood samples were taken from individuals with CPP and PT before the gonadotrophin-releasing hormone stimulation test and at 30, 60, 90 and 120min after injection with triptorelin. Results: Serum kisspeptin levels were higher in the CPP group when compared to the NC group (P=0.020), while serum MKRN3 levels lower in the two groups (P=0.028). There were no significant differences between the CPP and PT groups as well as the PT and NC groups (all, P<0.05). The cut-off value of serum kisspeptin differentiating patients with CPP from those without CPP was 0.40nmol/L, with 82.4% sensitivity and 57.1% specificity; while the cut-off value of serum MKRN3 was 0.33pmol/L, with 79.4% sensitivity and 53.6% specificity. The area under the curves (AUCs) of both kisspeptin and MKRN3 for differentiating those girls with CPP from PT were less than 0.5. Conclusions: Serum levels of kisspeptin and MKRN3 may play an auxiliary role in predicting CPP. However, the two measurements were not able to differentiate girls with CPP from PT and prepubertal control. This study emphasizes the need to search for markers to simplify the accurate diagnosis of CPP in girls.

Diagnostic Efficacy of Pelvic Ultrasound in Central Precocious Puberty in Girls: a Retrospective Cohort Study

Background: Differentiating central precocious puberty (CPP) patients from normal cases and CPP-like patients “isolated premature thelarche (IPA) and isolated premature thelarche (IPT)” is important for beginning of treatment. Although the GnRH stimulation test is considered the gold standard for diagnosis of CPP, Because of its wide limitations, our study targets to evaluate pelvic sonography parameters as a contributory tool for CPP diagnosis.Methods: We consecutively enrolled 183 cases (93 CPP, 16 IPT, 12 IPA and 62 of age-matched normal controls) in our study over four years. All cases are classified by clinical and laboratory findings and are followed up for at least 2 years. Pelvic sonography parameters included uterine fundus, body and cervix anteroposterior diameter, fundus/cervix ratio, uterine length and transverse diameter, uterine volume, endometrial thickness, ovarian volumes and diameter of the largest follicle are evaluated in all classified groups. One-way ANOVA, post hoc and receiver operating characteristic (ROC) analysis was used to compare the study groups.Results: Our study found that all sonography parameters differ significantly between CPP and normal control cases, also a significant difference is found between CPP compared to IPT or IPA cases in all parameters except in cervix anteroposterior diameter, ovarian volumes and diameter of the largest follicle. In order of best parameters for differentiating CPP compared to study groups, uterine volume (a cut-off of 1.40 ml had a sensitivity of 75.27% and a specificity of 75.56%), transverse diameter (a cut-off of 13.5 mm had a sensitivity of 72.04% and a specificity of 71.11%) and F/C ratio (a cut-off of 0.98 had a sensitivity of 78.49% and a specificity of 70%) was selected. Our study also classified sonography parameters as in equal diagnostic value to uterine volume (as the best diagnostic parameter with area under the curve of 0.826) and not equal diagnostic value to uterine volume.Conclusions: Pelvic Sonography parameters may improve the diagnosis of CPP patients and can have a contributory role in distinguishing treatment needed patients from other patients. The best diagnostic parameter and its cut-off value could change according to different ethnicities and studies.

Duplication of the Pituitary Gland (DPG)-Plus Syndrome Associated With Midline Anomalies and Precocious Puberty: A Case Report and Review of the Literature

Duplication of the pituitary gland (DPG)-plus syndrome is a very rare developmental disorder with few cases described in the literature and characterized by multiple midline and central nervous system malformations. The hypothalamus and hypophysis involvement may be clinically associated with endocrine abnormalities. A 5.9-year-old female child was admitted to our Clinic for premature thelarche and acceleration of growth. DPG-plus syndrome with paired infundibula and pituitary glands was diagnosed after birth, when she appeared small for gestational age and she presented with lingual hypoplasia, cleft palate, right choanal stenosis, nasopharyngeal teratoma, and facial dysmorphisms. Neuroimaging revealed a duplication of the infundibula, the pituitary gland, and the dens of the epistropheus despite surgical removal of a rhino-pharyngeal mass performed at the age of two months. An array-CGH revealed a 2p12 deletion. At our evaluation, bone age assessment resulted advanced and initial pubertal activation was confirmed by Gonadotropin-Releasing Hormone stimulation test. Hormonal suppression treatment was started with satisfactory results. This case shows that DPG-plus syndrome must be considered in presence of midline and craniofacial malformations and endocrinological evaluations should be performed for the prompt and appropriate management of pubertal anomalies.

Premature thelarche in an infant girl with failure to thrive related to dietary soy exposure

A 7-month-old female infant presented with failure to thrive. She was breastfed till 3 months of age, thereafter switched to soy-based milk formula. There was no history to suggest excess energy losses, recurrent infections or chronic diarrhoea. Three months after switching to exclusive soy-based milk formula, parents noticed significant enlargement of both breasts. Clinical examination was unremarkable except for enlargement of both breasts. None of the other secondary sexual characteristics were present. Initial blood investigations showed hyponatraemic hypokalaemic hypochloraemic metabolic alkalosis, which corrected after 2 days with intravenous hydration. The patient subsequently maintained normal electrolyte balance with recommended intake of cow’s milk-based standard formula milk.Further exploration of her soy-based milk revealed that it was low in sodium and calories, unsuitable for children. This was not a standard and approved infant soy-based formula milk. She achieved excellent weight gain and reduction of breast size on cessation of soy-based milk formula.

Sensitivity and specificity of using pelvic ultrasonographic parameters combined with basal gonadotropin levels to diagnose central precocious puberty in Thai girls

Background The criterion standard gonadotropin-releasing hormone (GnRH) stimulation tests to diagnose central precocious puberty (CPP) are time-consuming, inconvenient, and expensive. Objectives To determine predictive cut-off values codetermined by ultrasonographic parameters and basal gonadotropin levels in girls with premature sexual development and compare them results of criterion standard tests in a study of diagnostic accuracy. Methods Retrospective review of hormonal investigations and ultrasonographic uterine and ovarian parameters in a consecutive sample of girls at a single center, tertiary care hospital in Bangkok, Thailand. Results We separated data from 68 girls (age range 2–12 years) into 2 groups based on their response to a GnRH analogue agonist stimulation test. A “prepubertal response” group included girls with premature thelarche and thelarche variants (n = 18, 6.37 ± 1.77 years) and a “pubertal response” group, including girls with CPP (n = 50, 8.46 ± 1.46 years); excluding patients with pathological causes (n = 0). The basal level of luteinizing hormone (LH) had the largest area under receiver operating characteristic curves (AUC) of 0.84; 95% confidence interval [CI] 0.74–0.93) compared with basal levels of follicle stimulating hormone (AUC 0.77; 95% CI 0.64–0.90) or estradiol (0.70; 95% CI 0.56–0.85). An optimal cut-off of 0.25 IU/L LH was related to a pubertal response to GnRH analogue agonist stimulation tests with 75.0% sensitivity, 88.9% specificity, 94.7% positive predictive value (PPV), and 57.1% negative predictive value. Uterine and ovarian cut-off volumes of 3.5 cm3 and 1.5 cm3 were related to a pubertal response with 88.6% and 76.2% PPV, respectively. A uterine width cut-off of 1.7 cm combined with a basal LH cut-off of 0.25 IU/L increased specificity and PPV to 100%. Conclusion Combining uterine and ovarian ultrasonographic parameters with basal gonadotropin levels, especially uterine width and basal LH level, appears useful for diagnosis of CPP.